Deprotonation and hydride shifts in nitrenium and iminium forms of aminoimidazole-azaarene mutagens.
The mutagenicity of many 2-aminoimidazole-azaarenes (AIA) is thought to be mediated by the nitrenium form of the exocyclic amine. This hypothesis is supported by the numerous correlations found between calculated and experimentally-measured chemical properties for the nitreniums and the mutagenic potencies of the nitreniums and their parent amines. One factor favoring high mutagenic potency is the presence of a methyl substituent in the 1- or 3-imidazole position. In this paper, we investigate both the deprotonation of the imidazole ring nitrogens in non-N-methylated AIA mutagens and the plausibility of a chemical pathway involving a 1-4 hydride shift to form an iminium ion, thereby stabilizing the cationic N-methyl substituted AIA mutagens. It has been widely noted that factors that stabilize the nitrenium moiety lead to significantly higher mutagenic potency; hence, the transformation of the nitrenium to a more stable species might be expected to increase the potency, provided that it does not eliminate the electrophilic reactivity of the compound. Using ab initio quantum chemistry and polarizable continuum solvation models, we find that the imidazole ring nitrogens of the nitrenium ions are extremely acidic. This suggests that upon formation of the exocyclic nitrenium these sites will deprotonate to form a neutral imine. We have also studied the 1-4 hydride shift from an imidazole ring methyl to the exocyclic nitrenium to form an iminium. We predict that for AIA mutagens with just two fused rings the resulting iminium species are more stable in the gas phase than the corresponding nitreniums. For mutagens with larger conjugated systems, the nitrenium is stabilized by resonance and is more stable than the corresponding iminium. In the aqueous phase, however, the iminium form is predicted to be more stable than the nitreniums for all polycyclic compounds studied. Although equilibrium calculations favor the iminium form, these have been experimentally shown to be short-lived and their actual concentration will depend on the complex kinetics of AIA mutagen metabolism. The quantum chemical results also show a strong correlation between the relative iminium-nitrenium energy difference and the charge on the exocyclic nitrogen.
Colvin
M E
ME
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermmore, CA 94550, USA. colvin@gutenberg.llnl.gov
Seidl
E T
ET
Nielsen
I M
IM
Le Bui
L
L
Hatch
F T
FT
D001372:Aza Compounds / Q000737:chemistry*; D005609:Free Radicals / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry* / Q000633:toxicity; D007097:Imines / Q000737:chemistry*; D016297:Mutagenesis, Site-Directed; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity; D011522:Protons; D011789:Quantum Theory
D001372:Aza Compounds; D005609:Free Radicals; D007093:Imidazoles; D007097:Imines; D009153:Mutagens; D011522:Protons; C014973:2-aminoimidazole